There is a well established association between clinically apparent coronary heart disease (CHD) and autoimmune connective tissue diseases (CTD) including rheumatoid arthritis and lupus, but the exact mechanism is not established. It has been proposed that the association between CTD and CHD is related to common inflammatory processes. CTD-related autoantibodies have been identified in individuals years before they develop rheumatoid arthritis and lupus, but most individuals with positive circulating autoantibodies do not develop clinical CTD. Circulating autoantibodies have also been identified in CHD, thus it has been hypothesized that autoimmunity may contribute to the pathogenesis of atherosclerosis. However, it is not definitively known if subclinical CTD-related autoantibodies are associated with atherosclerosis and future clinical CHD. Preliminary data from this team suggest that there is an association between CTD-related antibodies and subclinical atherosclerosis: We found that the presence of anti-22 glycoprotein I antibodies (anti-22-GPI) measured in stored serum from African American (AA) and Caucasian young adults was associated with coronary artery calcification (CAC) measured 8 and 13 years later. We wish to extend this innovative finding in order to 1) determine if this relationship exists in other race/ethnicity groups, in other age groups and with other autoantibodies and 2) confirm the temporal relationship between subclinical CTD-related autoantibodies and CAC and extend our work to assess the relationship with ensuing clinical cardiovascular disease (CVD) events. To test our hypothesis that subclinical CTD-related autoantibodies lead to subclinical atherosclerosis and clinical CVD, we propose the following Aims using an existing cohort of 6814 multi-ethnic middle-aged to elderly subjects who will have active CTDs ruled out by a questionnaire: 1) Determine the cross-sectional association between subclinical CTD-related autoantibodies measured in stored sera collected at baseline (years 2000-2001) and presence of CAC. 2) Determine the association between baseline subclinical CTD-related autoantibodies and incidence, as well as progression, of CAC over 2 and 4 years follow-up. 3) Determine the association between baseline autoantibodies and clinical CVD events over 10 years follow-up. 4) Assess whether autoantibodies are associated with higher levels of inflammatory markers, and whether the relationship between autoantibodies and CVD outcomes are mediated by differences in inflammatory markers. These Aims will be accomplished by a team of investigators in the Division of Rheumatology and Department of Preventive Medicine at Northwestern University. We will utilize the ongoing multicenter Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort of 6814 Caucasian, AA, Hispanic, and Asian subjects followed since 2000 to examine the early stages of CVD in a multi-ethnic population. With its stored sera, epidemiologic database, older age, and multi-ethnicity, MESA is an ideal resource for this proposed study, which may lead to new approaches for the prevention of CVD. PUBLIC HEALTH RELEVANCE: The studies proposed here offer innovation and efficiency to the study of cardiovascular risk. The large sample size and the evaluation of autoantibodies will allow the principal investigator to address the unique hypothesis that subclinical autoantibodies are a risk factor for subclinical atherosclerosis and clinical cardiovascular disease. If in fact autoantibodies are found to be independently associated with subclinical atherosclerosis and clinical cardiovascular events, then information gained from this study may be used in the future to identify pertinent risk factors for cardiovascular disease so that primary and secondary prevention measures can be implemented.